Objective: This review article presents a comprehensive overview of the distinctions between two enduring autoimmune disorders: Rheumatoid arthritis (RA) and Ankyliosing spondylitis (AS), both of which affect the musculoskeletal system. The article highlights the differences in clinical manifestations, underlying mechanisms, and treatment approaches for these conditions. Methodology: This study is conducted by reviewing on google scholar using keywords such as RA and AS. Discussion: The article emphasizes that the key differences between these conditions lie in the affected body areas, genetic predisposition, and joint involvement. While RA mainly affects peripheral joints with inflammation of synovial tissues, AS primarily impacts the axial skeleton, leading to the fusion of spinal structures. RA has a strong autoimmune component, whereas AS is linked to HLA-B27. Treatment strategies differ, with RA benefiting from DMARDs and biologics, while AS relies on NSAIDs and TNF inhibitors. Understanding these distinctions is vital for accurate diagnosis and effective treatment planning. A patient’s quality of life may be significantly impacted by either of disease, underscoring the importance of early intervention and a multidisciplinary approach. Tailoring management to individual patient needs, considering factors like disease severity, comorbidities, and patient preferences, is essential. Regular monitoring, physical therapy, and lifestyle adjustments play crucial roles in managing these chronic conditions.